Betahistine hydrochloride tablet and preparation method thereof
Through the one-step granulation process of fluidized bed mixing, the preparation process of betastine hydrochloride tablets is simplified, and the existing wet mixing granulation methods are solved, and the efficient and low-cost preparation process and stable product quality are achieved.
Patent Information
- Application Number
- CN202410399109.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2023-12-22
- Filing Date
- 2024-04-03
- Publication Date
- 2025-06-24
AI Technical Summary
In the existing preparation methods of betastine hydrochloride tablets, the wet mixing granulation process is complex, with many processes and requires more manpower transfer, resulting in low production efficiency and high cost.
The one-step granulation process of fluidized bed mixing is used to simplify the process and set specific fluidized bed parameters, including fan frequency, material and air inlet temperature, atomization pressure, etc., to achieve rapid spraying and drying, and reduce preparation cycle and cost.
It has achieved efficient preparation of betastine hydrochloride tablets, with simple processes, high production efficiency, low cost, and stable and reliable product quality.
Smart Images
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Abstract
Description
Technical Field
[0001] This application relates to the field of pharmaceutical preparations, and particularly to a betahistine hydrochloride tablet and a preparation method thereof. Background Art
[0002] Betahistine hydrochloride is a drug developed by Formenti Pharmaceuticals S.p.A. in Italy. It is an agonist of the histamine H1 receptor and mainly has the effects of dilating capillaries, relaxing precapillary sphincters, increasing the blood flow in precapillary microcirculation, and relaxing the precapillary sphincters in the inner ear. It is mainly used for dizziness, tinnitus, etc. caused by chronic ischemic cerebrovascular diseases, cerebral arteriosclerosis or hypertension. The chemical name of betahistine is N-methyl-2-pyridin-2-ylethylamine, and its structural formula is , which is a white or off-white crystalline or crystalline powder. Betahistine hydrochloride is easily absorbed orally. Research shows that the blood drug concentration reaches the peak 3 to 5 hours after oral administration, and it is widely metabolized in the liver. The metabolites include at least two kinds, 2-pyridineacetic acid and 2-pyridineethylamine. The vast majority of betahistine after oral administration is usually excreted through the kidneys in the form of metabolites within 3 days.
[0003] The betahistine hydrochloride tablet is a widely used dosage form in betahistine hydrochloride preparations. The preparation method of the betahistine hydrochloride tablet is mainly wet granulation by mixing. The wet granulation by mixing process is simple, but there are many procedures in the wet granulation by mixing process, such as premixing, wet screening, drying, dry screening, mixing and other procedures. Among them, more manual transfer is required between procedures. This article aims to invent a preparation method with simple procedures.
[0004] If the direct compression mixing technology is used, some easily crystallized material particles are relatively large and are not easily mixed evenly with other excipients. This part of the material needs to be crushed, but the crushing process is more cumbersome, and the amount of material used in a single batch may be small. It is necessary to crush multiple batches of materials at one time, but it may not be used in a short time. Some materials are difficult to mix because they are strongly hygroscopic and absorb moisture in the air. Conventional mixers or wet granulation mixers are not easy to mix. Summary of the Invention
[0005] In order to solve the above problems, the present invention provides a preparation method of a betahistine hydrochloride tablet, and the preparation process is simple, the production efficiency is high, and the product quality is stable.
[0006] The present invention adopts fluidized bed mixing, with simple procedures, no need to add extra procedures and even can reduce procedures, short preparation cycle, low cost, high production efficiency, and high controllability of process parameters during the production process and stable product quality.
[0007] The present invention provides a betahistine hydrochloride tablet. The prescription of the betahistine tablet includes betahistine hydrochloride raw material medicine, microcrystalline cellulose and mannitol. The dosages of each component are as follows: 4 - 8 parts by weight of betahistine hydrochloride, 50 - 80 parts by weight of microcrystalline cellulose, and 10 - 40 parts by weight of mannitol.
[0008] Furthermore, the prescription also includes citric acid, colloidal silicon dioxide and talcum powder.
[0009] Even further, the dosage of citric acid in the prescription is 1 - 5 parts, the dosage of colloidal silicon dioxide is 1 - 5 parts, and the dosage of talcum powder is 3 - 10 parts.
[0010] The present invention provides a preparation method of a betahistine hydrochloride tablet. The method includes the following steps: (1) Weigh the prescribed amount of betahistine hydrochloride raw material medicine and citric acid and dissolve them in a solvent, and stir well to dissolve. (2) One-step granulation: Put microcrystalline cellulose and mannitol into the material tank of the fluidized bed, set the parameters of the process bed, preheat the material, and quickly spray the material in step (1) on the surface of the preheated material; after spraying all the liquid, continue drying until the moisture content is lower than 3% or below. (3) Screening, total mixing and tabletting: After discharging, screen the granules with a granule screening machine, add silicon dioxide and talcum powder to the screened granules and mix evenly, and then press the total mixed granules into tablets.
[0011] Furthermore, the parameters of the fluidized bed are set as follows: set the fan frequency to 1 - 15 Hz, the material temperature to 40 - 50 °C, the inlet air temperature to 50 - 70 °C, turn on the heating function, when the material temperature reaches 40 - 50 °C, adjust the atomization pressure to 1.0 - 2.0 bar, start spraying the liquid, and finish spraying all the liquid within 5 minutes.
[0012] Furthermore, the parameters of the fluidized bed in the drying step are set as the material temperature of 50 °C, the inlet air temperature of 70 °C, the fan frequency of 10 - 25 Hz, start drying, when the material temperature reaches 50 °C, take a sample, use a moisture meter to detect the moisture content of the granules, and stop drying and discharge the material until the moisture content is less than 3.0%.
[0013] Furthermore, the above-mentioned plain tablets are bottled or packaged with aluminum-plastic plates. Beneficial effects
[0014] In the prior art, wet granulation is generally used to prepare betahistine hydrochloride tablets. The wet mixing granulation process is simple, but its mixing and granulation processes are numerous, including pre-mixing, wet screening, drying, dry screening, mixing and other processes, and a large amount of manual transfer is required between processes. The present invention provides a method for preparing betahistine hydrochloride tablets by one-step granulation using a fluidized bed. By using fluidized bed mixing and setting specific fluidized bed parameters, the process is simple. Compared with the traditional wet granulation, the fluidized bed granulation process has fewer steps, a shorter preparation cycle, lower costs, higher production efficiency, and higher controllability of process parameters during production, and the quality of the products produced is stable and reliable.
[0015] The excipients of the betahistine hydrochloride tablets of the present invention are microcrystalline cellulose, mannitol, citric acid monohydrate, colloidal silicon dioxide and talc powder. The microcrystalline cellulose is used as a filler, mannitol as a disintegrant, citric acid monohydrate as a buffer, colloidal silicon dioxide as a glidant, and talc powder as a lubricant. The betahistine hydrochloride tablets prepared using the above components have good stability and dissolution that meets the quality standards. Detailed implementation manners
[0016] To make the objectives, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below. Those not specified in the embodiments are carried out according to conventional conditions or conditions recommended by the manufacturer. Those reagents or instruments not specified by the manufacturer can all be obtained as conventional products through commercial purchase. Embodiment 1
[0017] Prepare betahistine hydrochloride tablets according to the following prescription.
[0018]
[0019] The specific preparation steps are as follows: (1) Weigh the prescribed amount of betahistine hydrochloride raw material and citric acid and dissolve them in a solvent, and stir well until dissolved; (2) One-step granulation: Put microcrystalline cellulose and mannitol into the material tank of the fluidized bed, set the fluidized bed parameters, preheat the material, and quickly spray the material in step (1) on the surface of the preheated material; after the spraying is completed, continue drying until the moisture content is lower than 3% or less; the fluidized bed parameters are set as follows: set the fan frequency at 1-15 Hz, the material temperature at 40-50 °C, the inlet air temperature at 50-70 °C, turn on the heating function, and when the material temperature reaches 40-50 °C, adjust the atomization pressure to 1.0-2.0 bar, start spraying the liquid, and finish spraying all the liquid within 5 minutes. The fluidized bed parameters for the drying step are set with the material temperature at 50 °C, the inlet air temperature at 70 °C, the fan frequency at 10-25 Hz, start drying, when the material temperature reaches 50 °C, take a sample, use a moisture analyzer to detect the moisture content of the granules, and stop drying and discharge the material until the moisture content is less than 3.0%.
[0020] (3) Granulation, blending and tableting: After discharging, the granules are sized by a granulator. After sizing, silicon dioxide and talc powder are added to the sized granules and mixed evenly, and then the blended granules are compressed into tablets.
[0021] The above-mentioned step also includes bottling or aluminum-plastic board packaging of the above-mentioned plain tablets. Example 2
[0022] Betahistine hydrochloride tablets are prepared according to the following prescription.
[0023]
[0024] The specific preparation steps are as follows: (1) Weigh the prescribed amount of betahistine hydrochloride raw material and citric acid and dissolve them in a solvent, and stir well to dissolve; (2) One-step granulation: Put microcrystalline cellulose and mannitol into the material tank of the fluidized bed, set the parameters of the process bed, preheat the material, and quickly spray the material in step (1) on the surface of the preheated material; after spraying the material, continue drying until the moisture content is lower than 3% or below; the fluidized bed parameters are set as follows: set the fan frequency at 1 - 15 Hz, the material temperature at 40 - 50 °C, the inlet air temperature at 50 - 70 °C, turn on the heating function, when the material temperature reaches 40 - 50 °C, adjust the atomization pressure to 1.0 - 2.0 bar, and start spraying the liquid, and spray all the liquid within 5 minutes. The fluidized bed parameters for the drying step are set as the material temperature at 50 °C, the inlet air temperature at 70 °C, the fan frequency at 10 - 25 Hz, start drying, when the material temperature reaches 50 °C, take a sample, use a moisture analyzer to detect the moisture content of the granules, and stop drying until the moisture content is less than 3.0%, and then discharge the material.
[0025] (3) Granulation, blending and tableting: After discharging, the granules are sized by a granulator. After sizing, silicon dioxide and talc powder are added to the sized granules and mixed evenly, and then the blended granules are compressed into tablets.
[0026] The above-mentioned step also includes bottling or aluminum-plastic board packaging of the above-mentioned plain tablets.
[0027] Comparative Example 1 Preparation of betahistine hydrochloride tablets by wet granulation Using the prescription of betahistine hydrochloride tablets as described in Example 1, it is prepared by the following steps: (1) Premixing: Put the prescribed amount of microcrystalline cellulose, betahistine hydrochloride, mannitol, and citric acid monohydrate into a wet granulation mixer, with a stirring speed of 120 rpm, a chopping speed of 1100 rpm, and mix for 300 s; (2) Adding binder: Set the stirring speed of the granulator at 60 rpm and the chopping speed at 1100 rpm, and add an appropriate amount of purified water within 180 s; (3)Granulation: Keep the stirring speed of the granulator at 60 rpm and the chopping speed at 1100 rpm, granulate for 55 - 65 s, and discharge the material.
[0028] (4)Wet screening: Put the wet granules after granulation into a pulverizer for wet screening; (5)Fluidized bed drying Set the equipment parameters: Set the inlet air temperature at 70 °C and the material temperature at 50 °C. Put the wet granules after screening into the fluidized bed material tank for drying. Start detecting the moisture content (detect at 105 °C with a rapid moisture analyzer) when the material temperature rises to 50 °C. Stop heating when the moisture content ≤ 3.0%. Discharge the material after the material temperature drops to about 40 °C; (6)Screening: Screen the granules after discharging with a screening machine; (7)Total mixing: Add silicon dioxide and talc powder to the granules after screening and mix evenly; (8)Tabletting: Compress the granules after total mixing into tablets; (9)Bottle-pack or aluminum-plastic board-pack the above-mentioned plain tablets.
[0029] In summary, the method for preparing betahistine hydrochloride tablets by one-step fluidized bed granulation in the present invention is significantly less than the wet granulation method, which will greatly save labor and time costs.
[0030] Example 3 Dissolution evaluation of tablets Dissolution method: Refer to the method in General Rules of the Fourth Part of Chinese Pharmacopoeia (2020 Edition), adopt the paddle method, take betahistine hydrochloride tablets 718900 as the reference substance, and conduct dissolution experiments under the conditions that the dissolution medium is pH 1.0, pH 4.5 and pH 6.8. The obtained dissolution results are shown in the following table. It can be seen from the dissolution results that the dissolution of the betahistine hydrochloride tablets prepared by the method of the present invention is consistent with that of the betahistine hydrochloride tablets reference substance.
[0031]
[0032] Example 4 Stability evaluation Carry out accelerated tests on the samples prepared in Examples 1 - 2, study under the conditions of 40 °C ± 2 °C and RH 75% ± 5%, and the test results are shown as follows. The results show that the betahistine hydrochloride tablets prepared by the method of the present invention pass the stability test under accelerated conditions.
[0033]
[0034] The above are only the preferred embodiments of the present application and are not intended to limit the present application. For those skilled in the art, various modifications and variations can be made to the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included within the protection scope of the present application.
Claims
1. A betahistine hydrochloride tablet, characterized in that: The betahistine tablets include betahistine hydrochloride raw material, microcrystalline cellulose and mannitol, and the dosage of each component is: 4-8 parts by weight of betahistine hydrochloride, 50-80 parts by weight of microcrystalline cellulose, and 10-40 parts by weight of mannitol.
2. A betahistine hydrochloride tablet according to claim 1, characterized in that: The formulation also includes citric acid, colloidal silicon dioxide and talc.
3. A betahistine hydrochloride tablet according to claim 2, characterized in that: In the prescription, the dosage of citric acid is 1-5 parts, the dosage of colloidal silicon dioxide is 1-5 parts, and the dosage of talc is 3-10 parts.
4. A method for preparing betahistine hydrochloride tablets as claimed in claims 1-3, characterized in that: The method comprises the following steps: (1) Weigh the prescribed amount of betahistine hydrochloride API and citric acid, dissolve them in the solvent, and stir thoroughly to dissolve; (2) One-step granulation: put microcrystalline cellulose and mannitol into the material tank of the fluidized bed, set the process bed parameters, preheat the material, and quickly spray the material in step (1) on the surface of the preheated material; after the material is sprayed, continue to dry until the moisture content is less than 3% or below; (3) Granulation, total mixing and tableting: The discharged granules are granulated by a granulator, silicon dioxide and talcum powder are added to the granules after mixing evenly, and then the total mixed granules are pressed into tablets.
5. The method for preparing betahistine hydrochloride tablets according to claim 4, characterized in that: The fluidized bed parameters are set as follows: set the fan frequency to 1-15 Hz, the material temperature to 40-50°C, the air inlet temperature to 50-70°C, turn on the heating function, and when the material temperature reaches 40-50°C, adjust the atomization pressure to 1.0-2.0 bar, start spraying, and spray all the liquid within 5 minutes.
6. The method for preparing betahistine hydrochloride tablets according to claim 4, characterized in that: The fluidized bed parameters of the drying step are as follows: setting the material temperature to 50°C, the air inlet temperature to 70°C, the fan frequency to 10-25Hz, and starting drying. When the material temperature reaches 50°C, sampling is performed and the moisture content of the particles is detected using a moisture meter. When the moisture content is less than 3.0%, drying is stopped and the material is discharged.
7. The method for preparing the betahistine hydrochloride tablets according to any one of claims 4 to 5, characterized in that: The step also includes packaging the plain tablets in bottles or aluminum-plastic plates.